Clinical Trials Review

Abstract Each year fewer drugs are being approved by the FDA, yet the pharmaceutical industry is spending astronomical amounts developing new compounds. Modifications in the clinical trial process are needed in order to encourage the development of new possible therapeutics and bring new drugs onto the market. Reviewing the necessity of animal modeling, the institution of phase 0 and adaptive trial designs, improvement in patient recruitment, and collaboration between industry and academia are suggested as possible solutions to improve the number of compounds entering clinical trials.

This review paper will discuss the successes and drawbacks of these solutions. Introduction In the past decade, drug development has significantly decreased as fewer new drugs are arriving to market despite increased research and development spending. In 2010, despite only 15 new molecular entities were approved by the FDA compared to 53 in 1996, 39 in 1997, and 30 in 19981. The increasing expenses of developing new drugs as well as stricter approval standards by the FDA is deterring companies from creating new medicines2.

Therefore changes to the clinical trial process are needed make them more flexible, economical, and quicker to prevent the further decline in development of drugs. Current method of Clinical trails The modern clinical trial consists of six stages. These are in vitro studies, phase 0(first in man), 1 (safety and toxicity), 2(efficacy), 3(compared to current treatment), and 4 (post approval). In vitro studies need to be carried out on two animal models, the most common being mice however other animals can be used ranging from worms to zebra fish3.

These animal models are used to evaluate absorption, distribution, metabolism, excretion and toxicity of compound before testing in humans3. If appropriate the compound in small doses (approximately one tenth of therapeutic dose) can be tested in phase 0 to obtain preclinical data in healthy humans or patients, often between 10-15 subjects12. Pharmacokinetic and pharmacodynamics data are gathered however if small enough doses are given than they may not be able to be assayed limiting phase 0 data.

After phase 0, phase 1 trials are conducted in small groups (<100) of healthy humans to monitor safety and again pharmacokinetics and pharmacodynamics6. Then phase 2 trials are undertaken in larger groups (<300) to determine efficacy and toxic effects6. Large patient groups are recruited in phase 3 trials randomized to receive the new therapy either with or in comparison to the current therapy6. After the drugs passes the phase 3 trial and is reviewed by the FDA, it receives a notice of compliance (NOC) and can be put on the market.

Phase 4 is often called post marketing monitoring as it occurs after release to ensure safety and efficacy of drug. The current clinical trial process alone takes over ten years, about 802 million dollars per drug, and is highly failure prone as 80% of drugs fail between phase 3 and market3. Hence modifications are needed to the clinical trial process to reduce time and spending on compounds while encouraging more compounds to be taken to clinical testing. Animal Models.

Animal models have been successful in modeling disease progressions, through identifying the drug targets and revealing adverse drug reactions before the drug is further developed however focus has been mainly on selectivity and efficacy4. This focus causes many compounds to be excluded from clinical trials as it is not financially feasible to pursue these leads that are non-selective or have low efficacy further. Scientists need to be more open-minded and understand the strengths and limitations when using animal models to simulate human conditions.

Furthermore considerations in results need to be given to the differences between humans and animals in anatomy, histology, physiology and system responses5. For example in sepsis, sensitivity is seen in humans to endotoxin however rodents are relatively tolerant to endotoxin which limits the ability to create a disease model in animals7. In an analysis of 22 clinical trials of sepsis, being put into the control treatment was a more significant in factor in determining mortality in rats than in humans (88% versus 39%)8. Results such as these suggest that positive effects seen in in vivo testing animals do not always occur in humans.

Skipping animal models in diseases that cannot be well modeled would be beneficial as focus could be placed on developing therapies for humans rather than animals leading to possibly less drugs failing from ineffectiveness in humans. If animal models are to be used than more information should be extracted from them so that at least a pharmaceutical profile of a drug could be designed as well as obtain realistic models of diseases and experimental protocols that could be applied to clinical trials. A field in which animals could be beneficial is in “co-clinical trials”9.

These are parallel clinical trials using both mice and humans in diseases in which mutations play a significant role could have a significant impact on both drug approval and for identifying the factors or drugs that cause response in mice which could then be applied to the paitent9. In general animal models can provide important data when used appropriately, however flexibility is needed in implementation so that compounds are not eliminated from the discovery process due to failure in animal models and so that better treatments for complicated diseases can be developed. Phase 0.

“Figure 1: Preclinical to clinical transition in phase 0 trials and the effect of phase 0 studies on the further development of novel anticancer agents. ”15 A new experimental approach called phase 0 came into effect on January 2006 when the FDA released a exploratory Investigational New Drug guidance10. These studies involve patients or healthy volunteers receiving very low yet still pharmacologically active doses of compounds. These doses allow for pharmacokinetic and pharmacodynamics data to be obtained to develop better designs of future trials and decide if further clinical development is should be pursued11.

A significant advantage of phase 0 trials is that potential therapeutics can be classified as possible treatments very early in clinical trials11. Phase 0 allows molecules that exhibit variable animal pharmacokinetics to be used in microdoses (1/100 of pharmacological dose in animals) in humans allowing for more compounds enter the clinical trial phase11.

Although this opens the door for more compounds, phase 0 trials are limited as they require a low toxicity and a wide therapeutic index in animal models as well an assay needs to be available or developed to obtain statistically significant results from 10 to 15 patients13. In the compound ABT-888 which is a PARP inhibitor in tumor cells, phase 0 trials provided important information in for dosing schedules and the appropriate starting dose14.

Furthermore phase 1 and phase 2 study designs were able to better organized and the decision to undertake phase 1 studies in parallel as a result from phase 0 data14. Hence not only does phase 0 provide another option to clinical trial process but it also improves future testing which could lead to increased positive results.

Potential ethical concerns with the development of phase 0 are important as essentially subjects are being exposed to possible adverse drug reactions without any personal benefit14. It is important to note that these therapies are targeted and not cytotoxic molecules significantly reducing the risk on behalf of the patients participating14. Hence as fewer and fewer drugs are being approved for marketing and spending is increasing astronomically, the phase 0 approach allows for an economically feasible way of allowing more compounds to reach the clinical trial phase while halting the testing of underperforming compounds earlier in development.

Patient Recruitment Recruitment of patients for studies provides a significant challenge in clinical trials. An analysis of 100 trials revealed that patient targets are met in less than a third of trials and half are awarded an extension because of failure to enroll patients on schedule16. Of the two groups that declined participation, one group (30%) was due protocol issues such as length of study and placebo15. The other (30%) labeled inconveniences such as being unable to travel to the clinic or take time off work as reasons not to participate17.

An important feature of the study was that only 3% declined due to financial reasons suggesting that compensation does not motivate participation17. If scientists and regulatory bodies improve the flexibility of trials as well as protocol to fit with patients values and lifestyles substantial increases in participation could occur. In another study, the main two reasons for participating were to help others in the future and because of trust in the doctor18. Interestingly trust in doctor was a main reason of declining participation which suggests that doctors have a significant role in recruiting study patients18.

Therefore to improve enrollment in trials, doctors need to keep up to date with new treatments and outreach from companies to doctors is essential to inform them of possible new therapies for their patients. When patients met with the clinical trial doctors their attitude, interpersonal, listening and communication skills were significant (21%) factors in patients accepting treatment18. This suggests possibility that not only are the right patients needed for clinical trials but also doctors with special attributes are as well.

If enrollment could improve in clinical trials even by small amounts of 2 to 3 percent, this could translate to completing a study in two years rather than three19! The completion could significantly speed up the process of approving drugs and improve the current standard of therapy. Lastly developing a database of patient records would significantly increase access to patients for researchers as they could now find specific patients that have specific mutations or diseases which their compound acts on then offer enrollment in their trial20.

Limitations of the databases would be that participation would be voluntary as it is unethical to access personal information of unknowing patients which could reduce enrollment in these databases. Clinical trial recruitment is often overlooked in improving the current clinical trial method, adapting methods and increasing enrollment could significantly speed up the time it takes compounds to arrive on the market and enable more trials to be undertaken. The Adaptive Clinical Trial Design.

In 2010, a draft guidance on adaptive design clinical trials by the FDA which prospectively planned the possibility for modification of multiple specified aspects of study designs and hypotheses based on analysis of data from subjects in the study 21. This allows for the researcher to correct mistakes made at trial initiation, select treatment(s) demonstrating response, use external sources in the trial, react earlier to responses and possibly could reduce development time and speed up the process of bringing promising compounds to market22.

I-SPY2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) is a significant adaptive trial design in breast cancer patients as it allows drugs to be removed, added, or moved to phase 3 without writing new protocols saving a significant amount of time for the researchers23. This trial provided effective development and discovery of drugs as well as drug combinations for inhibiting specific cancer types23.

A significant advantage this trial had was that it was able to adapt treatments using patient biomarkers and use potential compounds to attempt to initiate a response23. Another trial called BATTLE (biomarker-integrated approaches of targeted therapy for lung cancer elimination), researchers used patients biomarkers to enroll patients in one of the four treatments for phase one24. Then in the second phase researchers adapted treatment centred on which subtypes in phase one benefited from24. This flexibility allowed for those who were benefiting from treatments to remain on them while those who possibly could be transferred to them.

This would allow for compounds that are promising in specific disease states to be tested rather than having to continue those which are deemed ineffective. Through this, personalization of clinical therapies can be created allowing for more drugs to be used in certain circumstances which would lead to more drugs being approved for market. Important factors to determine if a compound could be effective in adaptive clinical trials are noticeable drug responses in short periods of time and applicability to longitudinal models so treatments could be forecasted for subjects25.

The approval of the adaptive trial design is an important step in increasing the amount of drugs that are brought to the clinical trial stage, however caution will be needed as these trials could create an operational bias towards treatments aswell as increase false positive results from continual tests on experimental data. Industry and Academia Partnerships “Figure 2: The current approach compared to the collaborative approach. ”26 Synergizing efforts of both pharmaceutical industry and academia to undertake combined approaches to clinical trials and research could eliminate the current bottleneck in drug development.

Academic institutions and industry although have different priories, together their expertise and knowledge to further the drug development process. The beginning of these efforts can be seen in the treatments of Alzheimer’s disease as pharmaceutical companies are facing a shortage of small molecule targets whereas academia is struggling to develop basic research leads into beneficial compounds26. A new approach of academia finding novel and unverified targets then industry developing data, target validation, and efficiency with which it can be further developed could lead to more compounds being pursued26.

This approach could be feasible as industry is often cautious of approaching basic research due to the high rate of failure, academia is more liberal in its approach to basic research27. Using discoveries of new targets, compounds and their roles in diseases by academia, industry could save significant costs in its research and development and undertake further testing on initial discoveries. Currently this method is being used in the Alabama Drug Discovery Alliance which is undertaking 14 different projects, however a few years will be needed to determine this success of this method 27.

Pfizer has began to start up Global Centers for Therapeutic Innovation (CTIs) at universities as well as fund post docs with the goal moving new compounds into human clinical trials within 5 years28. A significant factor in the agreements with the universities are that Pfizer would hold an exclusive option to patent a drug after proof of mechanism, this could limit academics work and freedom as after initial discoveries are made large companies could take them away from academia28. Industry and academia collaboration because of their different viewpoints could lead to conflicts in partnership.

Industry is mainly concerned with financial the gain a compound can provide. Industry funding could be used as leverage which could cause non-reporting of toxicity or negative results and the amplification of positive results29 . Hence transparency, independent review bodies and statisticians are needed to ensure that conflicts of interest are revealed and to improve the validity of these trials. Collaboration between industry and academia could be a significant step in improving drug development as the pooling of resources, funds and minds could allow for important insights, increased efficiency, and reduced costs during clinical trials.

Conclusion Already the clinical trial process has begun to become more flexible with institution of new methods and improvement on current ones. Ideas to improve the clinical trial process such as adaptive trial designs are extremely complex while others such as improving patient recruitment can be applied generally regardless of study. With increasing dollars being spent on developing drugs and less making it to market, new ideas are needed to improve the drug pipeline and reduce costs of development.

Slowly new ideas such as changing animal modeling, phase 0, adaptive trial designs, better patient recruitment and collaboration between industry and academia will hopefully begin to demonstrate benefits. However new ideas need to be thoroughly evaluated as though they may increase the amount of drugs arriving to market, they might not necessarily act in the best interests of patients who could suffer from the change of evaluation of their medicines. Bibliography 1. Mullard A. 2011 FDA drug approvals. Nature Reviews Drug Discovery 2012;11:91-94. 2. Malik N. Drug discovery: past, present and future Drug Discovery Today 2008;13:21-22. 3. Dickson M, Gagnon J P.

The costs of new drug discovery and development. Discovery Medicine 2004;4:172 – 179. 4. Plowman G. Drug Discovery; Animal models identified as a major hurdle in drug discovery and development. Pharmaceutical Business Week Newsletter2004;8:80. 5. Shah S, Federoff HJ. Drug discovery dilemma and Cura Quartet collaboration. Drug Discovery Today 2009;14: 21: 1006 – 1010. 6. Lesko LJ, Rowland M, Peck CC, Blaschke TF. Optimizing the science of drug development: opportunities for better candidate selection and accelerated evaluation in humans. Journal of Clinical Pharmacology 2000;40: 803.

7. Brealey D, Karyampudi S, Jacques TS, et al: Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. American Journal of Physiology Regulatory, Integrative and Comparative Physiology 2004; 286:491–497. 8. Eichacker PQ, Parent C, Kalil A, et al: Riskand the efficacy of anti-inflammatory agents:Retrospective and confirmatory studies of sepsis. American Journal of Respiratory Critical Care Medicine 2002;166:1197–1205. 9. Caterina N, Andrea L, Akash P, Lewis C, Pier P. The APL Paradigm and the “Co-Clinical Trial” Project. Cancer Discovery 2011;1:108–116. 10.

US Department of Health and Human Services, Food and Drug Administration. Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies. January 2006. http://www. fda. gov/cder/guidance/7086fnl. pdf. Accessed April 1st, 2012. 11. Kummar S, et al. Phase 0 Clinical Trials: Conceptions and Misconceptions. The Cancer Journal 2008;14: 3. 12. Garner CR, Lappin G. The phase 0 microdosing concept. The British Journal of Clinical Pharmacology 2006; 61:4 367–370. 13. Steps to consider in pharmacodynamic assay development. National Cancer Institute Developmental Therapeutics Program Web Site.

Available at: http://dtp. nci. nih. gov/docs/phase0/PharmacoDynamicAssaydeveloment. html. Accessed April 1, 2011. 14. Eliopoulos H, et al. Phase 0 Trials: An Industry Perspective. Clinical Cancer Research 2008;14:3683-3688. 15. Murgo AJ, Kummar S, Rubinstein L. Designing Phase 0 Cancer Clinical Trials. Clinical Cancer Research 2008; 14:3675-3682. 16. McDonald AM, Knight RC, Campbell MK, Entwistle VA, Grant AM, Cook JA, Elbourne DR, Francis D, Garcia J, Roberts I, Snowdon C. What influences recruitment to randomized controlled trials? A review of trials funded by two UK funding agencies. Trials 2006 ;7:7–9.

17. Brintnall-Karabelas J, Sung S, Cadman ME, Squires C, Whorton K, Pao M. Improving Recruitment in Clinical Trials: Why Eligible Participants Decline. Journal of Empirical Research on Human Research Ethics 2011;1:69-74. 18. Jenkins V, Fallowfield L. Reasons for accepting or declining to participate in randomized clinical trials for cancer therapy. British Journal of Cancer 2000; 82:1783–1788. 19. Cornell University. How to improve patient participation in clinical trials. Science Daily, September 2007. Available at: http://www. sciencedaily. com/releases/2007/09/070917115305. html. Accessed April 1st, 2012.

20. Newsham A C, Johnston C, Hall G, Leahy MG, Smith AB, Vikram A, et al. Development of an advanced database for clinical trials integrated with an electronic patient record system. Computers in Biology and Medicine 2011; 41:575-586 . 21. FDA Draft Guidance for Industry – Adaptive Design Clinical Trials for Drugs and Biologics. The United States Food and Drug Administration. Available at http://www. fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm201790. pdf. Retrieved April 1st 2012. 22. Chow S, Corey R. Benefits, challenges and obstacles of adaptive clinical trial designs.

Journal of Rare Diseases 2011;6:79. 23. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, and Esserman LJ. I-SPY 2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy. Clinical Pharmacology & Therapeutics 2009;86:97–100. 24. Gold KA, Kim ES, Lee JJ, et al. The BATTLE to Personalize Lung Cancer Prevention through Reverse Migration. Cancer Prevention Research 2011;4:962-972. 25. Krams M, et al. Adaptive designs in clinical drug development: opportunities, challenges, and scope reflections following PhRMA’s November 2006 workshop.

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